SUGP2 (SURP and G-patch domain containing 2) is an mRNA splicing-related factor localized to nuclear bodies and the nucleoplasm that plays a critical role in RNA processing and transcription-replication coordination. Primary Function: SUGP2 functions as an RNA-binding protein involved in pre-mRNA splicing regulation 1. It regulates alternative splicing of specific transcripts, including CIRBP pre-mRNA, where it modulates splice site selection to control which mRNA isoforms are produced 1. Mechanism: SUGP2 is part of a nuclear protein network connecting replication fork machinery with transcription, splicing, and mRNA export components 2. It interacts with nucleoporins like Tpr and participates in protecting cells from RNA-mediated replication stress 2. Disease Relevance: Pathogenic SUGP2 variants, particularly p.(Arg639Gln), are associated with hemochromatosis through dysregulation of the CIRBP/BMPER/hepcidin iron-regulatory axis 1. This variant impairs normal CIRBP splicing, leading to altered iron homeostasis and increased hepatic iron accumulation 1. SUGP2 variants also appear in non-HFE hereditary hemochromatosis cases, often in combination with other BMP/SMAD pathway mutations 34. Clinical Significance: SUGP2 variants represent a novel genetic factor in primary iron overload disorders, identified in approximately 18.5% of Chinese hemochromatosis patients 1. Recognition of SUGP2-associated hemochromatosis may improve diagnosis and management of genetically heterogeneous iron overload disorders.